rs999662

Positions:

• chr16-56865596-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001126108.2(SLC12A3):​c.282+79T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0253 in 1,488,560 control chromosomes in the GnomAD database, including 620 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.028 (71 hom., cov: 33)
  • Exomes 𝑓: 0.025 (549 hom.)
• Consequence: SLC12A3 NM_001126108.2 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.40

Genes affected

SLC12A3 (HGNC:10912): (solute carrier family 12 member 3) This gene encodes a renal thiazide-sensitive sodium-chloride cotransporter that is important for electrolyte homeostasis. This cotransporter mediates sodium and chloride reabsorption in the distal convoluted tubule. Mutations in this gene cause Gitelman syndrome, a disease similar to Bartter's syndrome, that is characterized by hypokalemic alkalosis combined with hypomagnesemia, low urinary calcium, and increased renin activity associated with normal blood pressure. This cotransporter is the target for thiazide diuretics that are used for treating high blood pressure. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 16-56865596-T-G is Benign according to our data. Variant chr16-56865596-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 1208183.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-56865596-T-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0557 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC12A3	NM_001126108.2	c.282+79T>G		intron_variant		ENST00000563236.6	NP_001119580.2
SLC12A3	NM_000339.3	c.282+79T>G		intron_variant			NP_000330.3
SLC12A3	NM_001126107.2	c.282+79T>G		intron_variant			NP_001119579.2
SLC12A3	NM_001410896.1	c.282+79T>G		intron_variant			NP_001397825.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC12A3	ENST00000563236.6	c.282+79T>G		intron_variant		1	NM_001126108.2	ENSP00000456149.2
SLC12A3	ENST00000438926.6	c.282+79T>G		intron_variant		1		ENSP00000402152.2
SLC12A3	ENST00000566786.5	c.282+79T>G		intron_variant		1		ENSP00000457552.1
SLC12A3	ENST00000262502.5	c.282+79T>G		intron_variant		5		ENSP00000262502.5

Frequencies

GnomAD3 genomes AF: 0.0279 AC: 4250 AN: 152180 Hom.: 71 Cov.: 33

Gnomad AFR AF: 0.0303

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0474

Gnomad ASJ AF: 0.0158

Gnomad EAS AF: 0.0468

Gnomad SAS AF: 0.0610

Gnomad FIN AF: 0.0144

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0214

Gnomad OTH AF: 0.0287

GnomAD4 exome AF: 0.0250 AC: 33385 AN: 1336262 Hom.: 549 AF XY: 0.0261 AC XY: 17450 AN XY: 669706

Gnomad4 AFR exome AF: 0.0304

Gnomad4 AMR exome AF: 0.0445

Gnomad4 ASJ exome AF: 0.0142

Gnomad4 EAS exome AF: 0.0336

Gnomad4 SAS exome AF: 0.0587

Gnomad4 FIN exome AF: 0.0181

Gnomad4 NFE exome AF: 0.0214

Gnomad4 OTH exome AF: 0.0259

GnomAD4 genome AF: 0.0280 AC: 4264 AN: 152298 Hom.: 71 Cov.: 33 AF XY: 0.0293 AC XY: 2179 AN XY: 74480

Gnomad4 AFR AF: 0.0305

Gnomad4 AMR AF: 0.0474

Gnomad4 ASJ AF: 0.0158

Gnomad4 EAS AF: 0.0469

Gnomad4 SAS AF: 0.0615

Gnomad4 FIN AF: 0.0144

Gnomad4 NFE AF: 0.0214

Gnomad4 OTH AF: 0.0284

Alfa AF: 0.0220 Hom.: 19

Bravo AF: 0.0281

Asia WGS AF: 0.0500 AC: 174 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 02, 2019	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.24
DANN	Benign	0.65
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs999662; hg19: chr16-56899508;